Abstract: Leukodystrophies are inherited diseases that affect the white matter of the brain due to the loss or absence of myelin, the lipid membrane that insulates axons in the nervous systems. The leukodystrophy community is at a key turning point. Novel molecular approaches have increased disease recognition. At the same time key disorders now have potential treatment pathways. There is urgent unmet need in clinical trial readiness, lest the promise in pre-clinical development be unable to be translated to well-designed clinical trials. This gap in knowledge has galvanized stakeholders in the disease community. In collaboration with advocacy partners, we have formed a research-based consortium, the Global Leukodystrophy InitiAtive Clinical Trials Network (GLIA-CTN). In this proposal, the GLIA-CTN will embark on a longitudinal natural history, focused on but not limited to five leukodystrophy with clinical trial readiness: Adrenomyeloneuropathy (AMN), Aicard Goutieres Syndrome (AGS), Alexander Disease (AxD), Metachromatic Leukodystrophy and Pelizaeus Merzbacher Disease. Approaches will include Clinical Outcome Assessments (COA) and Patient Reported Outcomes (PRO) with a focus on reliability, reproducibility and validity. Additionally, we will develop methodology around Electronic Medical Record (EMR) extraction of natural history data for the leukodystrophies. Companion projects around novel tools and scales to define the ataxia seen in AMN, novel disease classification strategies in AGS and their correlation with disease severity and biomarkers, and evidentiary criteria around GFAP (glial fibrillary acidic protein) as a biomarker for AxD complete the proposal. Oversight for these projects will occur under a well-developed Administrative Unit which includes a Data Integration Core staffed by bioinformatics, epidemiologists and biostatisticians thanks to significant cost sharing with participating institutions. Sustainability of the program is supplemented with a strong career development and pilot project program. All aspects of the program are carefully aligned with our patient advocacy partners who have provided meaningful input and will be stakeholders in data sharing platforms. Together, these approaches will establish a platform to develop clinical trial readiness across the leukodystrophies, in close partnership between clinician scientists, advocacy groups and industry partners, enabling transformation of the field.